N-sulfinyl α-amino amides can be synthesized by the Strecker process [see, e.g., S. Mabic et al., Tetrahedron 57: 8861-8866 (2001); A. Plant et al., J. Org. Chem. 73: 3714-3724 (2008); F. A. Davis et al., J. Org. Chem. 65: 8704-8708 (2000)], which requires the use of highly poisonous cyanide anion and in which the resultant alpha-amino nitrile intermediate has to be hydrolyzed under harsh conditions to yield the corresponding alpha-amino amide. Because the hydrolysis of the nitrile prepared according to the Strecker process provides only a primary amide (—CONH2), the Strecker process is restricted to the synthesis of primary amides only.
The invention provides a highly diastereoselective process for making the N-sulfinyl α-amino amides of formula (I) which avoids the disadvantages of the Strecker synthesis.
It is known that the deprotonation of dialkylformamides (or dialkylthioformamides) affords carbamoyllithiums (or thiocarbamoyl lithiums). These carbamoyllithiums can then react with carbonyl electrophiles, thus allowing for the introduction of a carbamoyl group into carbonyl compounds. (See, e.g., D. Enders et al., Angew. Chem. Internat. Ed. 12:1014-1015 (1973) and B. Bánhidai et al. Angew. Chem. Internat. Ed. 12:836-836 (1973)). Reaction of carbamoyllithiums with sulfinimines as electrophiles has not been reported.
The inventors have found that carbamoyllithiums react with chiral, sterically hindered sulfinimines in a stereospecific manner to afford diastereomeric N-sulfinyl α-amino amides, which are useful as chiral building blocks for preparing pharmaceuticals.